Staphylococcus aureus biofilm: a complex developmental organism

Summary Chronic biofilm‐associated infections caused by Staphylococcus aureus often lead to significant increases in morbidity and mortality, particularly when associated with indwelling medical devices. This has triggered a great deal of research attempting to understand the molecular mechanisms that control S. aureus biofilm formation and the basis for the recalcitrance of these multicellular structures to antibiotic therapy. The purpose of this review is to summarize our current understanding of S. aureus biofilm development, focusing on the description of a newly‐defined, five‐stage model of biofilm development and the mechanisms required for each stage. Importantly, this model includes an alternate view of the processes involved in microcolony formation in S. aureus and suggests that these structures originate as a result of stochastically regulated metabolic heterogeneity and proliferation within a maturing biofilm population, rather than a subtractive process involving the release of cell clusters from a thick, unstructured biofilm. Importantly, it is proposed that this new model of biofilm development involves the genetically programmed generation of metabolically distinct subpopulations of cells, resulting in an overall population that is better able to adapt to rapidly changing environmental conditions. Novel technological advances that combine microfluidic flow‐cell systems with time‐lapse microscopy have greatly enhanced the visualization of biofilm development. Using this technology, our laboratory has revealed a more detailed view of the morphological stages and differential gene expression that occurs during Staphylococcus aureus biofilm development. Here, we review the complex molecular mechanisms that are required for each developmental stage and describe a new model for the formation of structure during biofilm maturation.